Design and Synthesis of Multimodal Lanthanide-based Nanoparticles for Bioapplications

摘要

Nanotechnology has allowed the fabrication of multifunctional nanoplatforms by integrating various components into a single nanoformulation. Their size compatibility with the biological systems and the development of efficient and flexible approaches that afford control to tailor the physical and chemical properties of these nanostructures with the ability to thoroughly characterize them facilitated a rapid rise in the use of nanoparticles as unique tools for many biological applications. In the clinic, these engineered nanoparticles, capable of diverse functionalities, hold great promise to a more individualized approach to management and therapies of various diseases. Combining contrasts for different imaging modalities in a single agent can give more accurate and detailed information on the physiological and anatomical characteristics of the disease pathology. Integration of imaging into the delivery of therapeutic agents offers a safer and more effective approach by ensuring sufficient accumulation in target tissues and by monitoring the effects both on the target and the surrounding healthy tissues.;Most fluorescent nanomaterials including quantum dots and dye-doped silica/gold nanomaterials are generally excited by ultraviolet (UV) or visible light that have limited penetration depth, induces autofluorescence and causes photodamage to cells with prolonged exposure. The remarkable property of the upconverting lanthanide-based nanoparticles to efficiently convert near infrared light (NIR) to shorter wavelengths circumvents these challenges. In addition, judicious choice of lanthanide composition allows the integration of several imaging modalities such as MRI and CT with added therapeutic modality.;The central theme of this thesis is design and development of lanthanide-based nanoparticles to yield multifunctional platforms advancing their suitability for research and clinical applications. A systematic approach to produce highly controlled hexagonal sodium lanthanide fluorides (NaLnF4) and the strategies used to fine tune the optical properties for high-contrast NIR in vivo optical imaging, and to serve as photon nanotransformer for precise control of light activated cellular functions are presented. The developed nanoformulation for optogenetics offers unprecedented opportunities for noninvasive control over neuronal circuitry of live animals by allowing localized emission of blue activating light through excitation of NIR light. This is a great advancement in optogenetics technology, which is severely hampered by the poor penetration of visible light in the deep brain regions, thus, requiring blue laser inserted into the brain of the animal.;Food and Drug Administration requires complete clearance of metal-containing nanoparticles in a reasonable amount of time to minimize the likelihood of potential toxicity. The large size of the nanoparticles and how it relates to normal physiology hinders their clinical translation. In general, nanoparticles with hydrodynamic diameter > 8 nm is rapidly captured by the macrophages of the reticuloendothelial system, resulting in a limited circulation time and inefficient clearance from the body. Here, ultrasmall, sub-5nm nanoparticles were developed to realize the promise of this nanoparticles for clinical use in image-guided radiotherapy. The combination of Gd and Yb in the nanocrystal yielded a bimodal probe for MRI and CT imaging with properties comparable to existing commercial agents (e.g. MagnevistRTM, iohexol). These high-Z lanthanides can also act as radiosensitizers by emitting low energy Auger electrons following radiotherapy by X-ray. Reducing the size of the nanoparticles allowed complete elimination from the body within days (i.e., 4 days) through hepatic and renal clearance as revealed from ICP-MS analysis of Gd3+.